DESCRIPTION: Though highly effective in changing the course of the global HIV epidemic, current Antiretroviral Therapy (ART) fails to eradicate the infection completely. This has led to the emergence of drug-resistant mutant strains, the phenomenon of latent disease and a number of adherence and toxicity issues associate with long-term therapy. Novel compounds that inhibit transcription from integrated viral genomes, thereby preventing the production of vira particles from stable viral reservoirs, present a valuable and differentiated therapeutic potential in the treatment of HIV. Tat, a potent transactivator of HIV gene expression essential for the synthesis of full-length transcripts of the integrated viral genome by RNA polymerase II, is a highly sought after transcription target for the treatment of HIV. Innovation: Didehydro-cortistati A (dCA), a representative of the cortistatin class of compounds, has demonstrated significant potential as a potent inhibitor of Tat. Preliminary Data: dCA has been shown to inhibit acute HIV-1 replication, has demonstrated additive effect of viral inhibition when combined with ART, and has been found to highly impact latent viremia in CD4+T cells of virally suppressed patients receiving ART for at least three years. However, dCA has been shown to have off target activity that impacts its safety profile in HIV therapy, including potent anti-angiogenesis effect. Specific Aims: The goal of this proposal is the design of a lead cortistatin agent that retains Tat inhibitin activity, has drug-like properties, and has a desirable safety and tolerability profile including te reduction of off-target anti-angiogenesis activity. In Specific Aim 1, we will synthesize 100-200 structurally divergent cortistatin analogs, test them for their ability to inhibit HIV-1 Tat activiy, and conduct cellular toxicity determination in uninfected HeLa CD4 cells. In Study Aim 2, we will characterize lead-like cortistatin analogs for antiangiogenic activity and drug-like properties including solubility, human plasma protein binding, liver microsomal stability, and CYP P450 inhibition. In Specific Aim 3, promising synthetic analogs that display potent Tat inhibition, diminutive anti-angiogenesis activity, and adequate in vitro drug-like properties will undergo HIV inhibition studies and mechanistic studies to confirm promising analogs' mechanism of action. This Phase I study will culminate in the generation of a pre-clinical candidate for Phase I investigation.